Multiple sclerosis (MS) is considered an immune-mediated disorder of the central nervous system (CNS) characterized by multifocal areas of inflammation and demyelination. Lesion formation depends on migration of lymphocytes from the systemic compartment into the CNS through the blood-brain barrier. We have defined molecular and functional properties of human brain derived microvascular endothelial cells and of T lymphocytes that regulate the migration process and analysed how changes in these properties, in response to inflammatory conditions, contribute to the pathogenesis of multiple sclerosis. Rates of migration of T lymphocytes derived from patients with MS across either a fibronectin and/or endothelial cell barrier in vitro were increased compared to cells obtained from healthy controls. In the MS patients, migration rate correlated with disease activity, defined by clinical and MRI criteria and with IFN gamma production by T cells. Migration was reduced in patients receiving current therapies for MS. Adhesion molecules, chemokines and matrix metalloproteinases were all found to regulate the migration of MS derived lymphocytes through proteins of the basement membrane and human brain endothelial cells. We further demonstrated that the migratory properties of lymphocytes and both permeability and chemokine production by human brain endothelial cells, can be regulated via signalling through the specific kinin B1 receptor that is up-regulated on lymphocytes and human brain endothelial cells during inflammation, providing a potential novel therapeutic approach to modulate lymphocyte-endothelial cell interactions.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.37815 |
| Date | January 2001 |
| Creators | Prat, Alexandre. |
| Contributors | Antel, Jack P. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Neurology and Neurosurgery.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001803251, proquestno: NQ70131, Theses scanned by UMI/ProQuest. |
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